Qiu Manman, Zhang Qicheng, Li Rui, Wei Rongrong, Zhao Jiawei, Tan Juan, Zhang Hongkai, Qiao Wentao
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China.
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
Cell Death Discov. 2025 Aug 23;11(1):402. doi: 10.1038/s41420-025-02702-7.
Oncolytic viruses represent an innovative strategy for cancer therapy. However, extensive gene expression reprogramming within tumor cells may hinder viral propagation by affecting essential cell-virus interactions. Here, through genome-wide CRISPR/Cas9 library screening, Suppressor of variegation 3-9 homolog 2 (SUV39H2), a histone methyltransferase, was identified as a critical factor in mediating resistance to oncolytic herpes simplex virus 1 (oHSV-1) in oral squamous cell carcinoma (OSCC). Functional studies in SCC15 cells revealed that SUV39H2 knockdown facilitated viral replication, while its overexpression suppressed it. The inhibitor OTS186935 targeting SUV39H2 was administered to evaluate its effects on viral replication both in vitro and in vivo. Pretreatment with OTS186935 in SCC15, SCC7, and MCF7 led to a significant enhancement of viral replication. Combined treatment with OTS186935 and oHSV-1 demonstrated significant anti-tumor efficacy in BALB/c nude mice bearing SCC15 tumors. SUV39H2 was shown to regulate the trimethylation of lysine 9 on histone 3 (H3K9me3) at the viral promoter regions of immediate-early gene ICP0, ICP4 and early gene ICP8, thereby repressed viral gene transcription. However, oHSV-1 infection induced the degradation of SUV39H2, a process mediated by the viral protein ICP0 through the proteasomal pathway. Findings from studies in SCC7 cells further supported the observation that SUV39H2 knockdown enhanced viral replication. Moreover, SUV39H2 downregulation increased CD4+ and CD8+ T cell infiltration in syngeneic tumors treated with oHSV-1. TCGA database analysis revealed that SUV39H2 is associated with distinct immune cell infiltration patterns across different cancer types and correlates with immune checkpoint expression. These results highlight the role of SUV39H2 in regulating oHSV-1 replication and indicate that SUV39H2 may represent a potential target to improve the efficacy of oncolytic virotherapy.
溶瘤病毒是一种创新的癌症治疗策略。然而，肿瘤细胞内广泛的基因表达重编程可能会通过影响关键的细胞-病毒相互作用来阻碍病毒的传播。在此，通过全基因组CRISPR/Cas9文库筛选，组蛋白甲基转移酶异染色质蛋白1（SUV39H2）被确定为口腔鳞状细胞癌（OSCC）中介导对溶瘤单纯疱疹病毒1（oHSV-1）耐药的关键因素。在SCC15细胞中的功能研究表明，敲低SUV39H2可促进病毒复制，而其过表达则抑制病毒复制。给予靶向SUV39H2的抑制剂OTS186935以评估其在体外和体内对病毒复制的影响。在SCC15、SCC7和MCF7细胞中用OTS186935预处理可显著增强病毒复制。OTS186935与oHSV-1联合治疗在携带SCC15肿瘤的BALB/c裸鼠中显示出显著的抗肿瘤疗效。研究表明，SUV39H2可调节即刻早期基因ICP0、ICP4以及早期基因ICP8病毒启动子区域组蛋白H3第9位赖氨酸的三甲基化（H3K9me3），从而抑制病毒基因转录。然而，oHSV-1感染可诱导SUV39H2降解，这一过程由病毒蛋白ICP0通过蛋白酶体途径介导。在SCC7细胞中的研究结果进一步支持了敲低SUV39H2可增强病毒复制这一观察结果。此外，SUV39H2下调增加了接受oHSV-1治疗的同基因肿瘤中CD4+和CD8+T细胞浸润。TCGA数据库分析显示，SUV39H2与不同癌症类型中不同的免疫细胞浸润模式相关，并与免疫检查点表达相关。这些结果突出了SUV39H2在调节oHSV-1复制中的作用，并表明SUV39H2可能是提高溶瘤病毒疗法疗效的潜在靶点。
